(adapted from the applicant's abstract): Arrhythmia's resulting from a disturbance of automaticity are a significant cause of brady- and tachy- arrhythmias and morbidity in-patients with heart disease. Limitations in pacemaker and pharmacologic treatment of these conditions are well known. Pharmacologic treatment of arrhythmia's will be improved through rational drug design targeted to specific proteins in which the identity, structure, and biophysics are known. The molecular basis of K+ channels that contribute to normal and abnormal automaticity remains elusive. In addition to the existence of multiple K+ channel types, significant differences in channel distribution in the atrium are suggested by the substantial regional differences in repolarization and response to external interventions. In this regard, different patterns of current expression have recently been demonstrated in human atria cells. This suggests that differential patterns of gene expression may exist in the atrium, which could have a profound influence on therapeutic strategies for atria arrhythmia's. Recent molecular studies have demonstrated that mutations of h-erg (human-erg-related gene) are responsible for a form of the familial long QT syndrome and might encode for IKr. However, a variety of discrepancies between the properties of the heterologously expressed h- erg and native IKr, leave the mechanistic link between defect and disease unresolved. The central hypotheses of this proposal is that Ikr is an essential component of the generation of normal and abnormal automaticity, that erg, likely in combination with other alpha and beta sub-units, forms the molecular basis of IKr, and that heterogeneous distribution of erg channels in the atrium may be functionally important. The applicant proposes to carry our a combined voltage-clamp study of IKr in isolated ferret atria and SA nodal myocytes and of an f-erg clone expressed in ocytes or mammalian cell lines.